The match is set to kick off at 10:15 am ET (7:15 am PT) and will be streamed live on ESPN+ (Catch all LaLiga matches across ESPN's family of networks).
The clash between LaLiga's most successful clubs will still have plenty of starpower on both sides, with Madrid striker Karim Benzema facing off against Barca defender Gerard Pique and United States youngster Sergino Dest.
Barca has struggled out the gates this season since Messi left for Paris Saint-Germain on a free agent move this summer, with manager Ronald Koeman already on the hot seat amid a lackluster string of results.
League-leading Madrid have started the campaign on solid footing under Carlo Ancelotti in his second stint as club manager following Zinedine Zidane's departure in the offseason.
The Catalan side will hope to stop a dubious skid against Los Blancos, with their only home victory over Madrid since 2015 being a 5-1 thumping in October 2018.
Messi won't be the only key figure now missing out on one of sports' greatest rivalries, with ex-Madrid stalwart Ramos having also made the move to PSG. Both players are tied at the top of most appearances in El Clasico with 45 each.